Pharmacokinetics of Topical Ocular Drug Delivery: Potential Uses for the Treatment of Diseases of the Posterior Segment and Beyond

Abstract

In developing a drug delivery strategy, issues of absorption, distribution, metabolism, and elimination must be considered. The eye presents unique opportunities and challenges when it comes to the delivery of pharmaceuticals, and is most accessible to the application of topical medications. While absorption by this route is inefficient, there are few side effects. While it has been assumed that topically applied drugs penetrated into the intraocular environment through the cornea, this is currently being reassessed. More recent investigations have shown that the conjunctival route of entry plays an important role in the penetration of drugs into the anterior segment. Furthermore, topically applied drugs have been shown to have access to the sclera from the conjunctiva. As such, it is conceivable that such drugs could find their way to the posterior segment. Data suggest that the sclera is readily permeable to even large molecular weight compounds ( approximately 150 kD). The recent finding that topically applied nepafenac inhibited choroidal and retinal neovascularization by decreasing the production of VEGF, as well as our data showing that even a large molecular weight peptide like insulin can accumulate in the retina and optic nerve after topical application, supports the contention that topically applied drugs can not only reach the posterior segment, but that they can also be therapeutic. Finally, the implications of our findings that topically applied insulin also accumulates in the contralateral eye as well as in the central nervous system are discussed.

Potential penetration of topical ranibizumab (Lucentis) in the rabbit eye

“…Past studies indicate that molecules as large as whole antibodies (150 kDa) are permeable to the sclera. 16,17 These larger molecules are thought to pass through the limbal conjunctival epithelium and then diffuse through the sclera, which is 15-25 times more permeable than the cornea. 17 Evidence for trans-scleral penetration to the posterior segment for smaller sized antibody fragments has been growing in recent literature.…”

“…16,17 These larger molecules are thought to pass through the limbal conjunctival epithelium and then diffuse through the sclera, which is 15-25 times more permeable than the cornea. 17 Evidence for trans-scleral penetration to the posterior segment for smaller sized antibody fragments has been growing in recent literature. 14,15 Three pieces of evidence in this experiment support a trans-scleral rather than a trans-corneal route of entry into the rabbit eye following q2h application.…”

Drug bioavailability from topically applied ocular drops. Does drop size matter?

“…Ocular contact time, and hence the bioavailability, of a drug can be enhanced by increasing the viscosity of the ophthalmic formulation. The addition of viscolysers, substances with high molecular weight, which barely cross biological membranes, prolongs the retention time of the instilled fluid [34]. Human tears have a viscosity of about 1.5 mPa·s.…”

Targeted Drug Delivery to the Eye Enabled by Microneedles

“…However, the direct exposure of the eye to the outside environment results in the eye possessing natural barriers that prevents drugs from effectively penetrating the outer surface of the eye to reach their target intraocular sites. A few of these barriers include the complex nature of the tear fluid, the reflex of blinking and associated tear fluid drainage, clearance from lymphatic and blood flow within the conjunctiva, and diffusion-limited transport across the epithelial barriers of the cornea and conjunctiva (Koevary 2003;Urtti 2006). As an additional constraint, any pharmacological treatment procedure should not hinder the natural function of the eye.…”